Post-tetanic potentiation (PTP) is a form of short-term plasticity that lasts for tens of seconds following a burst of presynaptic activity. It has been proposed that PTP arises from protein kinase C (PKC) phosphorylation of Munc18-1, an SM (Sec1/Munc-18 like) family protein that is essential for release. To test this model, we made a knock-in mouse in which all Munc18-1 PKC phosphorylation sites were eliminated through serine-to-alanine point mutations (Munc18-1SA mice), and we studied mice of either sex. The expression of Munc18-1 was not altered in Munc18-1SA mice, and there were no obvious behavioral phenotypes. At the hippocampal CA3-to-CA1 synapse and the granule cell parallel fiber (PF)-to-Purkinje cell (PC) synapse, basal transmission was largely normal except for small decreases in paired-pulse facilitation that are consistent with a slight elevation in release probability. Phorbol esters that mimic the activation of PKC by diacylglycerol still increased synaptic transmission in Munc18-1SA mice. In Munc18-1SA mice, 70% of PTP remained at CA3-to-CA1 synapses, and the amplitude of PTP was not reduced at PF-to-PC synapses. These findings indicate that at both CA3-to-CA1 and PF-to-PC synapses, phorbol esters and PTP enhance synaptic transmission primarily by mechanisms that are independent of PKC phosphorylation of Munc18-1.

SIGNIFICANCE STATEMENT A leading mechanism for a prevalent form of short-term plasticity, post-tetanic potentiation (PTP), involves protein kinase C (PKC) phosphorylation of Munc18-1. This study tests this mechanism by creating a knock-in mouse in which Munc18-1 is replaced by a mutated form of Munc18-1 that cannot be phosphorylated. The main finding is that most PTP at hippocampal CA3-to-CA1 synapses or at cerebellar granule cell-to-Purkinje cell synapses does not rely on PKC phosphorylation of Munc18-1. Thus, mechanisms independent of PKC phosphorylation of Munc18-1 are important mediators of PTP.

强直后增强 (PTP) 是一种短期可塑性形式，在突触前活动爆发后持续数十秒。有人提出 PTP 源于 Munc18-1 的蛋白激酶 C (PKC) 磷酸化，Munc18-1 是一种对释放至关重要的 SM (Sec1/Munc-18 样) 家族蛋白。为了测试这个模型，我们制作了一个敲入小鼠，其中所有 Munc18-1 PKC 磷酸化位点通过丝氨酸到丙氨酸的点突变（Munc18-1SA 小鼠）被消除，我们研究了任一性别的小鼠。Munc18-1在Munc18-1SA小鼠中的表达没有改变，也没有明显的行为表型。在海马 CA3 到 CA1 突触和颗粒细胞平行纤维 (PF) 到浦肯野细胞 (PC) 突触处，除了与释放概率略有升高相一致的双脉冲促进的小幅下降外，基础传输基本正常。模拟二酰基甘油激活 PKC 的佛波酯仍然增加 Munc18-1SA 小鼠的突触传递。在 Munc18-1SA 小鼠中，70% 的 PTP 保留在 CA3-to-CA1 突触处，并且 PTP 的幅度在 PF-to-PC 突触处没有降低。这些发现表明，在 CA3 到 CA1 和 PF 到 PC 突触中，佛波酯和 PTP 主要通过独立于 Munc18-1 的 PKC 磷酸化的机制增强突触传递。并且 PTP 的幅度在 PF-to-PC 突触处没有降低。这些发现表明，在 CA3 到 CA1 和 PF 到 PC 突触中，佛波酯和 PTP 主要通过独立于 Munc18-1 的 PKC 磷酸化的机制增强突触传递。并且 PTP 的幅度在 PF-to-PC 突触处没有降低。这些发现表明，在 CA3 到 CA1 和 PF 到 PC 突触中，佛波酯和 PTP 主要通过独立于 Munc18-1 的 PKC 磷酸化的机制增强突触传递。

意义声明一种普遍形式的短期可塑性，强直后增强 (PTP) 的主要机制涉及 Munc18-1 的蛋白激酶 C (PKC) 磷酸化。这项研究通过创建一个敲入小鼠来测试这种机制，其中 Munc18-1 被一种不能被磷酸化的突变形式的 Munc18-1 取代。主要发现是海马 CA3 到 CA1 突触或小脑颗粒细胞到浦肯野细胞突触的大多数 PTP 不依赖于 Munc18-1 的 PKC 磷酸化。因此，独立于 Munc18-1 的 PKC 磷酸化的机制是 PTP 的重要介质。